1y7v

X-ray structure of human acid-beta-glucosidase covalently bound to conduritol B epoxide
(see also Treatment of Gaucher disease)

 The crystal structure of the human acid-β-glucosidase (acid-beta-glucosidase, glucocerebrosidase, GlcCerase, E.C. 3.2.1.45, colored yellow ) with covalently bound irreversible inhibitor cyclohexitol (conduritol-B-epoxide; CBE; shown in cyan with its hydroxyl groups are in red ) was solved. This structure reveals that binding of CBE to the active site does not induce a global conformational change in GlcCerase and confirms that Glu340 is the active-site catalytic nucleophile, because the distance between the cyclohexitol C1 atom and Glu340 Oε2 is 1.43 Å. The comparison between the active sites of GlcCerase and another representative of the glycohydrolase family - plant β-D-glucan glucohydrolase (1iev), reveals that CBE bound with this plant enzyme adopted the "chair" conformation, while with human GlcCerase, it is observed in a "boat" conformation, with hydrogen bonds to Asn234 Oδ1 and Nδ2, Glu340 Oε1, Trp179 Nε1, and Asp127 Oδ1 and Oδ2.

Only one of two alternative conformations of a pair of flexible loops (L1: Ser345–Glu349, and L2: Val394–Asp399) located at the entrance to the active site in native GlcCerase (1ogs) is observed in the GlcCerase-CBE structure, a conformation in which the active site is accessible to CBE (colored blue ), while these loops in the second (closed) conformation are colored magenta. In loop 2, a major structural change is observed in the positions of Asn396 and Phe397 , and in <scene name='1y7v/L1/6'>loop 1 a more limited difference is observed in the conformations of <scene name='1y7v/L1/7'>Lys346 and Glu349. Analysis of the dynamics of these two alternative conformations suggests that the two loops act as a lid at the entrance to the active site. The movies 1 and 2 illustrate the dynamics of the movement of these two loops (Refs 1,2).

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About this Structure
1Y7V is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference
1) X-ray structure of human acid-beta-glucosidase covalently bound to conduritol-B-epoxide. Implications for Gaucher disease., Premkumar L, Sawkar AR, Boldin-Adamsky S, Toker L, Silman I, Kelly JW, Futerman AH, Sussman JL, J Biol Chem. 2005 Jun 24;280(25):23815-9. Epub 2005 Apr 6. PMID:15817452

2) Acetylcholinesterase in motion: visualizing conformational changes in crystal structures by a morphing procedure., Zeev-Ben-Mordehai T, Silman I, Sussman JL., Biopolymers. 2003 Mar;68(3):395-406. PMID:12601798

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